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Background <p>Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer’s disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood–brain barrier—a major site of insulin receptor signaling and transport into the brain—remains unclear.</p> Methods <p>We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1&#xa0;h, followed by 100 nM insulin for 10&#xa0;min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models.</p> Results <p>In hCMEC/D3 cells, Aβ40 reduced insulin-stimulated Akt activation and converted insulin’s normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Because the iBMEC model did not show insulin-induced activation of PI3K–Akt signaling, mechanistic interpretation of Aβ effects on insulin-responsive signaling focused on hCMEC/D3 cells.</p> Conclusions <p>These findings identify acute Aβ40-sensitive impairment of insulin-responsive Akt signaling in hCMEC/D3 BBB endothelial cells. The results define candidate signaling nodes for further mechanistic study of Aβ effects on BBB insulin-signaling dysfunction.</p>

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Acute amyloid-β exposure disrupts insulin signaling in hCMEC/D3 blood–brain barrier endothelial cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Douglas A. Nelson,
  • Suresh K. Swaminathan,
  • Vaishnavi Veerareddy,
  • Hannah S. Seo,
  • Samira M. Azarin,
  • Krishna R. Kalari,
  • Karunya K. Kandimalla

摘要

Background

Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer’s disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood–brain barrier—a major site of insulin receptor signaling and transport into the brain—remains unclear.

Methods

We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models.

Results

In hCMEC/D3 cells, Aβ40 reduced insulin-stimulated Akt activation and converted insulin’s normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Because the iBMEC model did not show insulin-induced activation of PI3K–Akt signaling, mechanistic interpretation of Aβ effects on insulin-responsive signaling focused on hCMEC/D3 cells.

Conclusions

These findings identify acute Aβ40-sensitive impairment of insulin-responsive Akt signaling in hCMEC/D3 BBB endothelial cells. The results define candidate signaling nodes for further mechanistic study of Aβ effects on BBB insulin-signaling dysfunction.